Ethanol affects numerous physiological processes, including those involved in learning and memory. Considerable literature has documented the ability of ethanol to impair memory for events which occur during intoxication. More recently, we have shown that ethanol can actually facilitate memory for events occuring before its administration. Others have also reported that post-training ethanol improves memory, in rodents as well as in humans. Certain aspects of drug abuse, in particular the development and maintenance of drug tolerance, have been proposed to involve learning and memory processes. While investigators acknowledge the role of learning in an organism's response to ethanol, they are largely unaware of how effectively ethanol establishes and association between environmental cues and subsequent ethanol effects. Further investigation of how post-training ethanol facilitates memory processes will improve our understanding of these issues. Memory enhancement by post-training ethanol has been well established in both humans and animals, but virtually no studies have been conducted on the factors that modulate this effect, or on the mechanisms responsible for it. For a number of reasons, we suspect the ethanol is acting via the posterior pituitary peptide hormone, vasopressin (VP), to facilitate passive avoidance behavior in mice. Vasopressin and its synthetic analogs have been found to enhance memory in humans, and to improve the performance of animals in a number of behavioral paradigms, including passive avoidance. Futhermore, VP modifies a variety of physiological and behavioral responses to ethanol such as tolerance, withdrawal, and ethanol consumption. Our long-range objective is to understand the role of neurohypophyseal hormones in the effects of ethanol on memory processes. The basic hypothesis is that VP release may be involved in the facilitatory effects of post-training ethanol, while inhibition of VP and stimulation of oxytocin (OXY) may be related to the amnestic effects of pre-training ethanol. Studies outlined in the present application will determine how plasma VP and OXY levels fluctuate in response to ethanol administration, and how passive avoidance performance of mice correlates with the timing of ethanol administration and pattern of hormone release. The role of VP in mediating ethanol-induced memory enhancement will be tested by treating animals with VP receptor antagonists or VP antisera. Our studies will focus on the memory-facilitating effects of ethanol, but the results will be relevant to the amnestic effects of ethanol as well. Finally, preliminary studies have shown that the pituitary gland itself is a site of action of ethanol. A sophisticated in vitro superfusion system will be used to delineate mechanisms whereby ethanol regulates the release of VP and OXY from the isolated neurointermediate lobe.